Akirins Clarify NF-κB Signaling

Science Signaling  08 Jan 2008:
Vol. 1, Issue 1, pp. ec6
DOI: 10.1126/stke.11ec6

Once again, the fruit fly has proven an invaluable tool for revealing information about the immune responses involving the transcription factor nuclear factor κB (NF-κB), as Beutler and Moresco emphasize. Goto et al. performed a genome-wide RNA interference (RNAi) screen in cultured Drosophila S2 cells for genes required for NF-κB-dependent gene expression and found the gene CG8580, which they renamed Akirin (for the Japanese akiraka ni suru, meaning "making things clear"). The authors determined that Drosophila has a single Akirin gene, which is essential for viability, and there are two in mammals (Akirin1, which is not essential for viability in mice, and Akirin2, which is). Transfection experiments with tagged versions of the proteins indicated that Akirins are localized to the nucleus, and the nuclear localization signal is the only recognizable motif in these proteins. S2 cells in which Akirin was knocked down showed defective activation of gene expression in response to stimuli that activate the Imd pathway, which mediates immune response to Gram-negative bacteria through the activation of the NF-κB homolog Relish. In contrast, the response to signaling through the Toll pathway, which mediates the response to Gram-positive bacteria through the activation of the NF-κB homolog Dif was not affected. Epistasis experiments placed Akirin at the level of Relish in the Imd pathway. In flies, knockdown of Akirin led to decreased survival after Gram-negative bacterial infection. Analysis of Akirin1 or Akirin2 knockout mouse embryo fibroblasts (MEFs) suggested that Akirin2 was the homolog involved in NF-κB signaling downstream of Toll-like receptors (TLRs) or the tumor necrosis factor (TNF) receptor. Furthermore, the human Akirin2 protein rescued S2 cells from defective Imd signaling caused by knockdown of endogenous Akirin. MEFs deficient for Akirin2 showed impaired expression of a subset of NF-κB-regulated genes, yet stimulation of NF-κB DNA binding and degradation of the inhibitor protein IκBα was not impaired. These results suggest that in mice, as in the fly, Akirin2 acts at the same level as NF-κB, and it will be interesting to see whether these two proteins form a complex, as has been recently reported for ribosomal protein S3 and NF-κB (see related resource).

A. Goto, K. Matsushita, V. Gesellchen, L. El Chamy, D. Kuttenkeuler, O. Takeuchi, J. A. Hoffmann, S. Akira, M. Boutros, J.-M. Reichhart, Akirins are highly conserved nuclear proteins required for NF-κB-dependent gene expression in drosophila and mice. Nat. Immunol. 9, 97-104 (2008). [PubMed]

B. Beutler, E. M. Y. Moresco, Akirins versus infection. Nat. Immunol. 9, 7-9 (2008). [PubMed]